Abstract 3164: Molecular determination of the clonal relationship between multiple tumors in BRCA1/2-associated cancer patients has clinical relevance

PURPOSE Female BRCA1/2 mutation carriers commonly develop breast cancer and ovarian cancer. It is of utmost importance to know the clonal relationship between multiple tumor localizations, (multiple primaries or metastasized disease), since prognosis and treatment differ between these tumors and their metastases. We evaluated the value of targeted Next Generation Sequencing (NGS) in the diagnostic workup of BRCA1/2 mutation carriers with ≥2 tumor localizations and uncertain tumor origins. METHODS Forty-two female BRCA1/2 mutation carriers with ≥2 tumor locations with tumor material available for pathologic revision were selected. Median age at first cancer diagnosis was 48.0 years (range 30-68). Four patients with inconclusive tumor origin after histological and immunohistochemical analyses were ‘cases’; 10 patients with certain tumor origin of ≥3 tumors served as ‘controls’. Tumors of cases and controls were analyzed by targeted NGS using a panel including CDKN2A, PTEN and TP53, hotspot mutation sites for 27 different genes and 143 single nucleotide polymorphisms for detection of loss of heterozygosity (LOH). Based on prevalence of identical or different mutations and/or LOH patterns, tumors were classified as ‘multiple primaries’ or ‘one entity’. RESULTS In 44 tumors, 48 mutations were found; 39 (81%) concerned TP53 mutations. In all 10 controls and all 4 cases, the intrapatient clonal relationships between the tumors could be unequivocally identified by molecular analysis. In all controls, tumor origins based on molecular outcomes matched the conventional histopathological diagnosis. CONCLUSION In 90% of BRCA1/2 mutation carriers with multiple tumors routine pathology work-up is sufficient to determine tumor origins and relatedness. In case of inconclusive conventional pathology results, molecular analyses using NGS can reliably determine clonal relationships between tumors, enabling optimal treatment of individual patients. Citation Format: Willemina R.R. Geurts-Giele, Victorien M.T. van Verschuer, Carolien H.M. van Deurzen, Paul J. van Diest, Rute M. Pedrosa, J. Margriet Collee, Linetta B. Koppert, Caroline Seynaeve, Winand N.M. Dinjens. Molecular determination of the clonal relationship between multiple tumors in BRCA1/2-associated cancer patients has clinical relevance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3164.